The hGFAP-driven conditional TSPO knockout is protective in a mouse model of multiple sclerosis.
The hGFAP-driven conditional TSPO knockout is protective in a mouse model of multiple sclerosis.
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DOI：
10.1038/srep22556
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发表时间：
2016-03-01
影响因子：
4.6
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Daugherty DJ;Chechneva O;Mayrhofer F;Deng W
线粒体转位蛋白（TSPO）与中枢神经系统疾病有关。在这里，我们试图确定TSPO在实验性自身免疫性脑脊髓炎（EAE）中的具体作用，EAE是研究最多的多发性硬化症（MS）动物模型。为了从根本上阐明TSPO的功能，我们首先建立了一只存活的TSPO敲除小鼠。利用Cre-Lox系统构建条件TSPO基因敲除小鼠。我们制备了一只TSPO粘接小鼠，并将其与人类胶质纤维酸性蛋白（hGFAP）启动子驱动的表达Cre重组酶的小鼠杂交。由此产生的小鼠是一个神经谱系特异性TSPO敲除。中枢神经系统中TSPO的缺失不会导致明显的发育缺陷或表型。TSPO−/−小鼠显示GFAP表达减少，这与EAE期间神经损伤的星形胶质细胞增生减少有关。星形胶质细胞增生的减少也体现在EAE临床评分严重程度的减轻上，这表明TSPO在体内具有抑制EAE的功能作用。TSPO - / -小鼠可能是更好地理解TSPO在中枢神经系统疾病中的作用的有用工具，我们的结果表明TSPO是MS的潜在治疗靶点。
The mitochondrial translocator protein (TSPO) has been implicated in CNS diseases. Here, we sought to determine the specific role of TSPO in experimental autoimmune encephalomyelitis (EAE), the most studied animal model of multiple sclerosis (MS). To fundamentally elucidate the functions of TSPO, we first developed a viable TSPO knockout mouse. A conditional TSPO knockout mouse was generated by utilizing the Cre-Lox system. We generated a TSPO floxed mouse, and then crossed this mouse with a Cre recombinase expressing mouse driven by the human glial fibrillary acidic protein (hGFAP) promoter. The resultant mouse was a neural linage line specific TSPO knockout. The loss of TSPO in the CNS did not result in overt developmental defects or phenotypes. The TSPO−/− mouse showed a decrease in GFAP expression, correlating with a decrease in astrogliosis in response to neural injury during EAE. This decrease in astrogliosis was also witnessed in the lessening of severity of EAE clinical scoring, indicating an in vivo functional role for TSPO in suppressing EAE. The TSPO−/− mouse could be a useful tool in better understanding the role of TSPO in CNS disease, and our results implicate TSPO as a potential therapeutic target in MS.